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1.  PICH and BLM limit histone association with anaphase centromeric DNA threads and promote their resolution 
The EMBO Journal  2011;30(16):3309-3321.
PICH and BLM limit histone association with anaphase centromeric DNA threads and promote their resolution
The helicase proteins PICH and BLM localize to ultrafine DNA threads between separating sister chromatids. It now appears they cooperate to remove histones from these anaphase DNA bridges, to allow their stretching and unravelling without breakage.
Centromeres nucleate the formation of kinetochores and are vital for chromosome segregation during mitosis. The SNF2 family helicase PICH (Plk1-interacting checkpoint helicase) and the BLM (the Bloom's syndrome protein) helicase decorate ultrafine histone-negative DNA threads that link the segregating sister centromeres during anaphase. The functions of PICH and BLM at these threads are not understood, however. Here, we show that PICH binds to BLM and enables BLM localization to anaphase centromeric threads. PICH- or BLM-RNAi cells fail to resolve these threads in anaphase. The fragmented threads form centromeric-chromatin-containing micronuclei in daughter cells. Anaphase threads in PICH- and BLM-RNAi cells contain histones and centromere markers. Recombinant purified PICH has nucleosome remodelling activities in vitro. We propose that PICH and BLM unravel centromeric chromatin and keep anaphase DNA threads mostly free of nucleosomes, thus allowing these threads to span long distances between rapidly segregating centromeres without breakage and providing a spatiotemporal window for their resolution.
PMCID: PMC3160651  PMID: 21743438
centromere; chromatin remodelling; DNA repair; mitosis
3.  Measurement of serum procalcitonin levels for the early diagnosis of spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis 
It is difficult to diagnose spontaneous bacterial peritonitis (SBP) early in decompensated liver cirrhotic ascites patients (DCPs). The aim of the study was to measure serum procalcitonin (PCT) levels and peripheral blood leukocyte/platelet (WBC/PLT) ratios to obtain an early diagnostic indication of SBP in DCPs.
Our cohort of 129 patients included 112 DCPs (94 of whom had infections) and 17 cases with compensated cirrhosis as controls. Bacterial cultures, ascitic fluid (AF) leukocyte and peripheral WBC/PLT counts, and serum PCT measurements at admission were carried out prior to the use of antibiotics. Receiver operating characteristic (ROC) curves were generated to test the accuracies and cut-off values for different inflammatory markers.
Among the 94 infected patients, 66 tested positive by bacterial culture, for which the positivity of blood, ascites and other secretions were 25.8%, 30.3% and 43.9%, respectively. Lung infection, SBP and unknown sites of infection accounted for 8.5%, 64.9% and 26.6% of the cases, respectively. Serum PCT levels (3.02 ± 3.30 ng/mL) in DCPs with infections were significantly higher than those in control patients (0.15 ± 0.08 ng/mL); p < 0.05. We used PCT ≥0.5 ng/mL as a cut-off value to diagnose infections, for which the sensitivity and specificity was 92.5% and 77.1%. The area under the curve (AUC) was 0.89 (95% confidence interval: 0.84–0.91). The sensitivity and specificity were 62.8% and 94.2% for the diagnosis of infections, and were 68.8% and 94.2% for the diagnosis of SBP in DCPs when PCT ≥2 ng/mL was used as a cut-off value. For the combined PCT and WBC/PLT measurements, the sensitivity was 76.8% and 83.6% for the diagnosis of infections or SBP in DCPs, respectively.
Serum PCT levels alone or in combination with WBC/PLT measurements seem to provide a satisfactory early diagnostic biomarker in DCPs with infections, especially for patients with SBP.
PMCID: PMC4332920
Cirrhosis; Infection; Spontaneous bacterial peritonitis; Procalcitonin; Early diagnosis
4.  Clinical outcomes of CyberKnife stereotactic body radiotherapy for peripheral stage I non-small cell lung cancer 
The aim of this study was to evaluate the clinical outcome of CyberKnife stereotactic body radiotherapy (SBRT) for patients with stage I non-small cell lung cancer (NSCLC). Fifty patients with peripheral stage I NSCLC who refused surgery or were medically inoperable were treated with 48–60 Gy (median dose: 57 Gy) in three divided doses. Histopathology was available in 86 % of patients. Thirty patients had a T1 tumor, and 20 patients had T2 tumors. More than 95 % of the target volume was covered by the 72 % isodose surface. Fiducials were implanted in or near the tumors in all patients to track tumor movement and breathing patterns. The median follow-up time was 35 months (3–45 months). Based on computed tomography scans, 40 patients achieved complete remission, six patients achieved partial remission, two patients exhibited stable disease, and two patients had progressive disease. The local control rate (CR + PR) was 92 %, and the 2-year disease control rate (CR + PR + SD) was 96 %. Overall survival for the whole group was 86 % at 1 year and 74 % at 2 years. Grade III toxicity occurred in two patients (4 %) after marker placement. Treatment-related late grade III toxicity occurred in five patients (10 %). Toxicities greater than grade III were not observed. CyberKnife SBRT achieves a high rate of local control and long-term curative effect with acceptable toxicity for patients with inoperable stage I NSCLC. However, long-term follow-up is necessary to evaluate survival and late toxicity.
PMCID: PMC4312559  PMID: 25638468
NSCLC; CyberKnife; SBRT; Clinical outcomes
5.  Efficacy and Safety of Deep Anterior Lamellar Keratoplasty vs. Penetrating Keratoplasty for Keratoconus: A Meta-Analysis 
PLoS ONE  2015;10(1):e0113332.
To evaluate difference in therapeutic outcomes between deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP) for the clinical treatment of keratoconus.
A comprehensive search was conducted in Pubmed, EMBASE, Cochrane Library, and Web of science. Eligible studies should include at least one of the following factors: best corrected visual acuity (BCVA), postoperative spherical equivalent (SE), postoperative astigmatism and endothelial cell count (ECC), central corneal thickness (CCT), graft rejection and graft failure, of which BCVA, graft rejection and graft failure were used as the primary outcome measures, and postoperative SE, astigmatism, CCT and ECC as the secondary outcome measures. Given the lack of randomized clinical trials (RCTs), cohort studies and prospective studies were considered eligible.
Sixteen clinical trials involving 6625 eyes were included in this review, including 1185 eyes in DALK group, and 5440 eyes in PKP group. The outcomes were analyzed using Cochrane Review Manager (RevMan) version 5.0 software. The postoperative BCVA in DALK group was significantly better than that in PKP group (OR = 0.48; 95%CI 0.39 to 0.60; p<0.001). There were fewer cases of graft rejection in DALK group than those in PKP group (OR = 0.28; 95%CI 0.15 to 0.50; p<0.001). Nevertheless the rate of graft failure was similar between DALK and PKP groups (OR = 1.05; 95%CI 0.81 to 1.36; p = 0.73). There were no significant differences in the secondary outcomes of SE (p = 0.70), astigmatism (p = 0.14) and CCT (p = 0.58) between DALK and PKP groups. And ECC in DALK group was significantly higher than PKP group (p<0.001). The postoperative complications, high intraocular pressure (high-IOP) and cataract were analyzed, fewer cases of complications occurred in DALK group than those in PKP group (high-IOP, OR 0.22, 95% CI 0.11–0.44, P<0.001) (cataract, OR 0.22; 95% CI 0.08–0.61, P = 0.004). And no cases of expulsive hemorrhage and endophthalmitis were reported.
The visual outcomes for DALK were not equivalent to PKP. The rate of graft failure was similar between DALK and PKP. Fewer postoperative complications occurred in DALK group, indicating that compared with PKP, DALK has lower efficacy but higher safety.
PMCID: PMC4310590  PMID: 25633311
6.  An improved and robust DNA immunization method to develop antibodies against extra-cellular loops of multi-transmembrane proteins 
mAbs  2013;6(1):95-107.
Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry. As expected, the use of the immune modulators fetal liver tyrosine kinase 3 ligand (Flt3L) and granulocyte-macrophage colony-stimulating factor positively enhanced the immune response against MRP4. Imaging studies using CMV-based plasmids expressing luciferase showed that the in vivo half-life of the target antigen was less than 48 h using CMV-based plasmids, thus necessitating frequent boosting with DNA to achieve an adequate immune response. We also describe a comparison of plasmids, which contained MRP4 cDNA with either the CMV or CAG promoters, used for immunizations. The observed luciferase activity in this comparison demonstrated that the CAG promoter-containing plasmid pCAGGS induced prolonged constitutive expression of MRP4 and an increased anti-MRP4 specific immune response even when the plasmid was injected less frequently. The method described here is one that can be broadly applicable as a general immunization strategy to develop antibodies against multi-transmembrane proteins, as well as target antigens that are difficult to express or purify in native and functionally active conformation.
PMCID: PMC3929459  PMID: 24121517
monoclonal antibody; DNA immunization; multi-transmembrane proteins; MRP4
7.  Smoking-Related Knowledge, Attitude, Social Pressure, and Environmental Constraints among New Undergraduates in Chongqing, China 
Background: Smoking has resulted in numerous deaths in China. Data indicate that 21% of college students in China are smokers. Objective: This study aimed to examine the smoking-related behaviors of undergraduates, as influenced by knowledge, attitude, social pressure, and environmental constraints. Method: A convenience sampling of 412 fresh undergraduates from two universities in the University Town in Chongqing, China was recruited. Chi-square tests were used to compare the smoking-related variables between smokers and non-smokers. Moreover, logistic regression was used to examine the factors that associated with smoking status in undergraduates. Results: Smokers and non-smokers differ in terms of knowledge, attitudes toward smoking, participation in tobacco promotional activities, and sources of social pressure. Logistic regression model identified that sex, living cost, five smoking-related attitudes of “Smoking is pleasurable, Smoking relaxes me, Smoking makes me look strong, Smoking is a waste of money, Smoking can help me study better”, the social pressure “Smoking brings comfort during celebration”, and the environmental constraints “How did you get your cigarettes in the past 30 days?” are significantly associated with smoking. Conclusions: The findings provide a better understanding of the epidemic of smoking among fresh undergraduates in Chongqing, China. This study provides more detailed consideration of the implications for the WHO Framework Convention on Tobacco Control (FCTC) policies, especially on restriction of retail sales outlets and tobacco promotion activities near universities in China.
PMCID: PMC4306900  PMID: 25607600
undergraduates; smoking; attitude; environmental constraints; knowledge; social pressure
8.  Exercises in Hot and Humid Environment Caused Liver Injury in a Rat Model 
PLoS ONE  2014;9(12):e111741.
To investigate injury pattern during intense exercises in hot and humid environment particularly on liver in a rat exertional heat stroke model.
We randomly divided 30 rats into a control group (CG), a normal temperature (25±2°C, 60%±5% humidity) exercise group (NTEG) and a high temperature and high humidity (35±2°C, 80%±10% humidity) exercising group (HTEG), each comprising 10 animals. The NTEG and HTEG rats were forced to run in a treadmill for 1 hour maximum at 20 rpm. We analyzed liver cells of all three groups with JC-1 dye and flow cytometry for apoptosis rates in addition to liver tissue 8 - hydroxy deoxyguanosine (8 - OhdG) and blood serum IL–6, tumor necrosis factor alpha (TNF-α), alanine aminotransferase ALT, aspartate amino transferase (AST), serum creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), creatine phosphate kinase (CK) concentrations.
Compared with NTEG rats, beside reduced exercise tolerance (60±5 vs. 15±3 minutes) (p = 0.002) the 8-OhdG liver tissue concentrations were significantly higher (p = 0.040) in the HTEG rats. The HTEG developed more organ tissue damage and cellular fragmentations of liver cells. In both exercise groups TNF-α and IL-6 serum concentrations were enhanced significantly (p<0.001) being highest in the HTEG animals. Serum ALT, AST, LDH, CREA, BUN and CK concentrations were significantly enhance in both exercise groups.
In our exertional heat stroke rat model, we found tissue damage particularly in livers during exercises in hot and humid environment that was related to inflammation, oxidative stress and apoptosis.
PMCID: PMC4280227  PMID: 25548911
9.  A novel feature selection method and its application 
In this paper, a novel feature selection method based on rough sets and mutual information is proposed. The dependency of each feature guides the selection, and mutual information is employed to reduce the features which do not favor addition of dependency significantly. So the dependency of the subset found by our method reaches maximum with small number of features. Since our method evaluates both definitive relevance and uncertain relevance by a combined selection criterion of dependency and class-based distance metric, the feature subset is more relevant than other rough sets based methods. As a result, the subset is near optimal solution. In order to verify the contribution, eight different classification applications are employed. Our method is also employed on a real Alzheimer's disease dataset, and finds a feature subset where classification accuracy arrives at 81.3%. Those present results verify the contribution of our method.
PMCID: PMC4269276  PMID: 25530672
Alzheimer's disease; class-based distance metric; feature selection; mutual information; rough sets
10.  Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia 
According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.
PMCID: PMC4266232  PMID: 25498990
Molecular genetics; Chronic neutrophilic leukemia; Chronic myelomonocytic leukemia; Atypical chronic myeloid leukemia
11.  Use of Electrical Impedance Tomography to Monitor Regional Cerebral Edema during Clinical Dehydration Treatment 
PLoS ONE  2014;9(12):e113202.
Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content.
a prospective study.
In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank.
23 patients with brain edema.
The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes.
Measurement and Main Results
Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients' responses to such treatment.
EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients.
PMCID: PMC4256286  PMID: 25474474
12.  Simultaneous saccharification and fermentation of steam-exploded corn stover at high glucan loading and high temperature 
Biotechnology for Biofuels  2014;7(1):167.
Simultaneous saccharification and fermentation (SSF) is a promising process for bioconversion of lignocellulosic biomass. High glucan loading for hydrolysis and fermentation is an efficient approach to reduce the capital costs for bio-based products production. The SSF of steam-exploded corn stover (SECS) for ethanol production at high glucan loading and high temperature was investigated in this study.
Glucan conversion of corn stover biomass pretreated by steam explosion was maintained at approximately 71 to 79% at an enzyme loading of 30 filter paper units (FPU)/g glucan, and 74 to 82% at an enzyme loading of 60 FPU/g glucan, with glucan loading varying from 3 to 12%. Glucan conversion decreased obviously with glucan loading beyond 15%. The results indicated that the mixture was most efficient in enzymatic hydrolysis of SECS at 3 to 12% glucan loading. The optimal SSF conditions of SECS using a novel Saccharomyces cerevisiae were inoculation optical density (OD)600 = 4.0, initial pH 4.8, 50% nutrients added, 36 hours pre-hydrolysis time, 39°C, and 12% glucan loading (20% solid loading). With the addition of 2% Tween 20, glucan conversion, ethanol yield, final ethanol concentration reached 78.6%, 77.2%, and 59.8 g/L, respectively, under the optimal conditions. The results suggested that the solid and degradation products’ inhibitory effect on the hydrolysis and fermentation of SECS were also not obvious at high glucan loading. Additionally, glucan conversion and final ethanol concentration in SSF of SECS increased by 13.6% and 18.7%, respectively, compared with separate hydrolysis and fermentation (SHF).
Our research suggested that high glucan loading (6 to 12% glucan loading) and high temperature (39°C) significantly improved the SSF performance of SECS using a thermal- and ethanol-tolerant strain of S. cerevisiae due to the removal of degradation products, sugar feedback, and solid’s inhibitory effects. Furthermore, the surfactant addition obviously increased ethanol yield in SSF process of SECS.
PMCID: PMC4267439  PMID: 25516770
Corn stover biomass; High glucan loading; High temperature; Simultaneous saccharification and fermentation (SSF); Surfactant; Mass balance
13.  Development of the science of mass casualty incident management: reflection on the medical response to the Wenchuan earthquake and Hangzhou bus fire*  
Objective: In this paper, we review the previous classic research paradigms of a mass casualty incident (MCI) systematically and reflect the medical response to the Wenchuan earthquake and Hangzhou bus fire, in order to outline and develop an improved research paradigm for MCI management. Methods: We searched PubMed, EMBASE, China Wanfang, and China Biology Medicine (CBM) databases for relevant studies. The following key words and medical subject headings were used: ‘mass casualty incident’, ‘MCI’, ‘research method’, ‘Wenchuan’, ‘earthquake’, ‘research paradigm’, ‘science of surge’, ‘surge’, ‘surge capacity’, and ‘vulnerability’. Searches were performed without year or language restriction. After searching the four literature databases using the above listed key words and medical subject headings, related articles containing research paradigms of MCI, 2008 Wenchuan earthquake, July 5 bus fire, and science of surge and vulnerability were independently included by two authors. Results: The current progresses on MCI management include new golden hour, damage control philosophy, chain of survival, and three links theory. In addition, there are three evaluation methods (medical severity index (MSI), potential injury creating event (PICE) classification, and disaster severity scale (DSS)), which can dynamically assess the MCI situations and decisions for MCI responses and can be made based on the results of such evaluations. However, the three methods only offer a retrospective evaluation of MCI and thus fail to develop a real-time assessment of MCI responses. Therefore, they cannot be used as practical guidance for decision-making during MCI. Although the theory of surge science has made great improvements, we found that a very important factor has been ignored—vulnerability, based on reflecting on the MCI response to the 2008 Wenchuan earthquake and July 5 bus fire in Hangzhou. Conclusions: This new paradigm breaks through the limitation of traditional research paradigms and will contribute to the development of a methodology for disaster research.
PMCID: PMC4265562  PMID: 25471837
Mass casualty incident; Surge; Vulnerability; Earthquake; Fire incident
14.  Responses of beneficial Bacillus amyloliquefaciens SQR9 to different soilborne fungal pathogens through the alteration of antifungal compounds production 
Bacillus amyloliquefaciens SQR9 exhibited predominantly antagonistic activities against a broad range of soilborne pathogens. The fungi-induced SQR9 extracts possess stronger antifungal activities compared with SQR9 monoculture extracts. To investigate how SQR9 fine-tunes lipopeptides (LPs) and a siderophore bacillibactin production to control different fungal pathogens, LPs and bacillibactin production and transcription of the respective encoding genes in SQR9 were measured and compared with six different soilborne fungal pathogens. SQR9 altered its spectrum of antifungal compounds production responding to different fungal pathogen. Bacillomycin D was the major LP produced when SQR9 was confronted with Fusarium oxysporum. Fengycin contributed to the antagonistic activity against Verticillium dahliae kleb, Fusarium oxysporum, Fusarium solani, and Phytophthora parasitica. Surfactin participated in the antagonistic process against Sclerotinia sclerotiorum, Rhizoctonia solani, and Fusarium solani. Bacillibactin was up-regulated when SQR9 was confronted with all tested fungi. The reduction in antagonistic activities of three LP and bacillibactin deficient mutants of SQR9 when confronted with the six soilborne fungal pathogens provided further evidence of the contribution of LPs and bacillibactin in controlling fungal pathogens. These results provide a new understanding of specific cues in bacteria-fungi interactions and provide insights for agricultural applications.
PMCID: PMC4240174  PMID: 25484880
Bacillus amyloliquefaciens SQR9; transcriptional response; soilborne pathogens; lipopeptide antibiotics; bacteria-fungal interaction
15.  Genetic Identification and Risk Factor Analysis of Asymptomatic Bacterial Colonization on Cardiovascular Implantable Electronic Devices 
BioMed Research International  2014;2014:725163.
Asymptomatic bacterial colonization of cardiovascular implantable electronic devices (CIEDs) is widespread and increases the risk of clinical CIED infection. The aim of the study was to evaluate the incidence of bacterial colonization of generator pockets in patients without signs of infection and to analyze the relationship with clinical infection and risk factors. From June 2011 to December 2012, 78 patients underwent CIED replacement or upgrade. Exclusion criteria included a clinical diagnosis of CIED infection, bacteremia, or infective endocarditis. All patients were examined for evidence of bacterial 16S rDNA on the device and in the surrounding tissues. Infection cases were recorded during follow-up. The bacterial-positive rate was 38.5% (30 cases); the coagulase-negative Staphylococcus detection rate was the highest (9 cases, 11.5%). Positive bacterial DNA results were obtained from pocket tissue in 23.1% of patients (18 cases), and bacterial DNA was detected on the device in 29.5% of patients (23 cases). During follow-up (median 24.6 months), two patients (6.7%, 2/30) became symptomatic with the same species of microorganism, S. aureus and S. epidermidis. Multivariable logistic regression analysis found that the history of bacterial infection, use of antibiotics, application of antiplatelet drugs, replacement frequency, and renal insufficiency were independent risk factors for asymptomatic bacterial colonization.
PMCID: PMC4233659  PMID: 25530969
16.  Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents 
Molecular nutrition & food research  2013;57(11):2071-2074.
Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (1) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (2) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (3) a higher serum active GLP-1. Third, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (1) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and that (2) GLP-1 is important in the optimal feeding response to a fast.
PMCID: PMC3892668  PMID: 23818307
Aging; Brain function; GK; Glucose sensing; GLP-1; Resistant Starch
17.  Chromatin remodelers fine-tune H3K36me-directed deacetylation of neighbor nucleosomes by Rpd3S 
Molecular cell  2013;52(2):10.1016/j.molcel.2013.08.024.
Chromatin remodelers have been implicated in the regulation of histone modifying complexes. However the underlying mechanism remains poorly understood. The Rpd3S histone deacetylase complex is recruited by elongating RNA polymerase II to remove histone acetylation at coding regions in a manner that is dependent on methylation of lysine 36 on histone 3 (H3K36me), and Rpd3S prefers dinucleosomes. Here, we show that the binding of Rpd3S to dinucleosomes and its catalytic activity are sensitive to the length of nucleosomal linker in a nonlinear fashion. Intriguingly, we found that H3K36me on one nucleosome stimulates Rpd3S to deacetylate the neighboring nucleosomes when those two nucleosomes are within an optimal distance. Finally, we demonstrate that chromatin remodelers enhance Rpd3S activity by altering nucleosomal spacing, suggesting that chromatin remodelers prime chromatin configuration to fine-tune subsequent histone modification reactions. This mechanism is important for accurate temporal control of chromatin dynamics during the transcription elongation cycle.
PMCID: PMC3825818  PMID: 24055344
18.  Combined aberrant expression of N-Myc downstream-regulated gene 2 and CD24 is associated with disease-free survival and overall survival in patients with hepatocellular carcinoma 
Diagnostic Pathology  2014;9(1):209.
N-Myc downstream-regulated gene 2 (NDRG2), as a tumor suppressor, has been demonstrated to inhibit tumor invasion and migration of hepatocellular carcinoma (HCC) by reducing the expression of CD24, which has been identified as a prognostic factor for HCC patients. However, the clinical significance of combined NDRG2 and CD24 expression in HCC remains unclear. Thus, the aim of the current study was to investigate the relationship of NDRG2 and CD24 expression with clinicopathological parameters and patients’ survival.
Immunohistochemistry was performed to detect the expression and subcellular localizations of NDRG2 and CD24 proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues.
NDRG2 protein was strongly expressed in the cytoplasm and plasma membrane of hepatocytes in adjacent nonneoplastic liver tissues, whereas its immunostaining was weak or negative in HCC tissues. In contrast, CD24 protein exhibited the cytoplasm immunostaining in tumor cells of HCC tissues but showed negative expression in adjacent nonneoplastic liver tissues. The statistical analysis also showed that the expression levels of NDRG2 and CD24 proteins in HCC tissues were respectively lower and higher than those in adjacent nonneoplastic liver tissues significantly (both P < 0.001). In addition, there was an inverse correlation between NDRG2 expression and CD24 expression in HCC tissues (P = 0.02). Moreover, combined NDRG2 downregulation and CD24 upregulation (NDRG2-low/CD24-high) more frequently occurred in HCC tissues with high serum AFP (P = 0.03), advanced tumor stage (P = 0.001) and high tumor grade (P = 0.02). Furthermore, HCC patients with NDRG2-low/CD24-high expression showed shortest 5-year disease-free survival and 5-year overall survival (both P < 0.001) of four groups (NDRG2-low/CD24-high, NDRG2-low/CD24-low, NDRG2-high/CD24-high, NDRG2-high/CD24-low). Of note, the multivariate survival analysis showed that the combined aberrant expression of NDRG2 and CD24 proteins was an independent prognostic factor for both 5-year disease-free survival and 5-year overall survival (both P = 0.01) in HCC.
These findings suggest that the downregulation of NDRG2 combined with the upregulation of CD24 may play a synergistic role in the occurrence and progression of HCC. A combined detection of NDRG2/CD24 expression may benefit us in determining the prognosis in patients with HCC.
Virtual Slides
The virtual slide(s) for this article can be found here:
PMCID: PMC4212122  PMID: 25338637
N-Myc downstream-regulated gene 2; CD24; Hepatocellular carcinoma; Disease-free survival; Overall survival
19.  CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia 
The WHO 2008 definition of chronic neutrophilic leukemia (CNL) is based on clinical and laboratory parameters but not on molecular abnormalities. Mutations in CSF3R, SETBP1 and CALR are reported in patients with chronic neutrophilic leukemia (CNL). However, because CNL is rare, there are few large studies of this issue. We sequenced these genes in 14 patients who met the WHO-criteria of CNL. 8 subjects had CSF3RT618I, 6 SETBP1 mutations and 1 a CALR mutation. Our data suggest mutation analysis of CSF3R, SETBP1 and CALR should be included in the diagnostic criteria for CNL. These data may also have therapy implications.
PMCID: PMC4200198  PMID: 25316523
Chronic neutrophilic leukemia, CNL; CSF3R; SETBP1; CALR; Mutation
20.  ZMYND11 links histone H3.3 K36 trimethylation to transcription elongation and tumor suppression 
Nature  2014;508(7495):263-268.
Recognition of modified histones by “reader” proteins plays a critical role in the regulation of chromatin1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state thus suppressing cryptic transcription2. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies3. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analyses reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating Pol II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; low expression level of ZMYND11 in breast cancer patients correlates with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression.
PMCID: PMC4142212  PMID: 24590075
21.  Molecular Epidemiology and Clinical Characteristics of Drug-Resistant Mycobacterium tuberculosis in a Tuberculosis Referral Hospital in China 
PLoS ONE  2014;9(10):e110209.
Despite the large number of drug-resistant tuberculosis (TB) cases in China, few studies have comprehensively analyzed the drug resistance-associated gene mutations and genotypes in relation to the clinical characteristics of M. tuberculosis (Mtb) isolates.
Methodology/Principal Findings
We thus analyzed the phenotypic and genotypic drug resistance profiles of 115 Mtb clinical isolates recovered from a tuberculosis referral hospital in Beijing, China. We also performed genotyping by 28 loci MIRU-VNTR analysis. Socio-demographic and clinical data were retrieved from medical records and analyzed. In total, 78 types of mutations (including 42 previously reported and 36 newly identified ones) were identified in 115 Mtb clinical isolates. There was significant correlation between phenotypic and genotypic drug resistance rates for first-line anti-TB drugs (P<0.001). Genotyping revealed 101 MIRU-VNTR types, with 20 isolates (17.4%) being clustered and 95 isolates (82.6%) having unique genotypes. Higher proportion of re-treatment cases was observed among patients with clustered isolates than those with unique MIRU-VNTR genotypes (75.0% vs. 41.1%). Moreover, clinical epidemiological links were identified among patients infected by Mtb strains belonging to the same clusters, suggesting a potential of transmission among patients.
Our study provided information on novel potential drug resistance-associated mutations in Mtb. In addition, the genotyping data from our study suggested that enforcement of the implementation of genotyping in diagnostic routines would provide important information for better monitor and control of TB transmission.
PMCID: PMC4193878  PMID: 25302501
22.  Complete Genome Sequence of European Genotype Porcine Reproductive and Respiratory Syndrome Virus Strain LNEU12 in Northern China 
Genome Announcements  2014;2(5):e00957-14.
We report the complete genome sequence of a European genotype porcine reproductive and respiratory syndrome virus isolated from swine in northern China in 2012. Genome alignment revealed that the virus (LNEU12) strain shares 90.1% nucleotide identity with the European prototype Lelystad virus. Here, we announce the complete genome sequence of LNEU12.
PMCID: PMC4192376  PMID: 25301644
23.  Active gastrointestinal diverticulum bleeding diagnosed by computed tomography angiography 
World Journal of Gastroenterology : WJG  2014;20(37):13620-13624.
A diverticulum is a bulging sack in any portion of the gastrointestinal tract. Small intestine diverticular disease is much less common than colonic diverticular disease. The most common symptoms include non-specific epigastric pain and a bloating sensation. Major complications include diverticulitis, gastrointestinal bleeding, acute perforation, intestinal obstruction, intestinal perforation, localized abscess, malabsorption, anemia, volvulus and bacterial overgrowth. We report one case of massive jejunal diverticula bleeding and one case of massive colonic diverticula bleeding, both diagnosed by acute abdominal computed tomography angiography and treated successfully by surgery.
PMCID: PMC4188915  PMID: 25309094
Diverticulum; Gastrointestinal diverticular bleeding; Angiography; Computed tomography angiography; Endoscopy
24.  Loop-mediated isothermal amplification assays for screening of bacterial integrons 
Biological Research  2014;47(1):53.
The occurrence and prevalence of integrons in clinical microorganisms and their role played in antimicrobial resistance have been well studied recently. As screening and detection of integrons are concerned, current diagnostic methodologies are restricted by significant drawbacks and novel methods are required for integrons detection.
In this study, three loop-mediated isothermal amplification (LAMP) assays targeting on class 1, 2 and 3 integrons were implemented and evaluated. Optimization of these detection assays were performed, including studing on the reaction temperature, volume, time, sensitivity and specificity (both primers and targets). Application of the established LAMP assays were further verified on a total of 1082 isolates (previously identified to be 397 integron-positive and 685 integron-negative strains). According to the results, the indispensability of each primer had been confirmed and the optimal reaction temperature, volume and time were found to be 65°C, 45 min and 25 μL, respectively. As application was concerned, 361, 28 and 8 isolates carrying intI1, intI2 and intI3 yielded positive amplicons, respectively. Other 685 integron-negative bacteria were negative for the integron-screening LAMP assays, totaling the detection rate and specificity to be 100%.
The intI1-, intI2- and intI3-LAMP assays established in this study were demonstrated to be the valid and rapid detection methodologies for the screening of bacterial integrons.
PMCID: PMC4222780  PMID: 25418445
Loop-mediated isothermal amplification (LAMP); Integron screening; Bacterial integrons; Class 1 integron; Class 2 integron; Class 3 integron
25.  Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System 
The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structure-activity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF, encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF, together with its chaperone and cochaperone genes pscE and pscG, to a ΔpscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF.
PMCID: PMC4023729  PMID: 24468789

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